Comparing the prognostic performance of iBOX and biopsy-proven acute rejection for long-term kidney graft survival.

Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year, making superiority trials unfeasible. iBOX, a quantitative composite of estimated glomerular filtration rate, proteinuria, antihuman leukocyte antigen donor-specific antibody, and + full/- abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR's prognostic ability was compared with iBOX in a pooled cohort of 1534 kidney transplant recipients from 4 data sets, including 2 prospective randomized controlled trials. Discrimination analyses showed mean c-statistic differences between both iBOX compared with BPAR of 0.25 (95% confidence interval: 0.17-0.32) for full iBOX and 0.24 (95% confidence interval: 0.16-0.32) for abbreviated iBOX, indicating statistically significantly higher c-statistic values for the iBOX prognosis of death-censored graft survival. Mean (± standard error) c-statistics were 0.81 ± 0.03 for full iBOX, 0.80 ± 0.03 for abbreviated iBOX, and 0.57 ± 0.03 for BPAR. In calibration analyses, predicted graft loss events from both iBOX models were not significantly different from those observed. However, for BPAR, the predicted events were significantly (P < .01) different (observed: 64; predicted: 70; full iBOX: 76; abbreviated iBOX: 173 BPAR). IBOX at 1-year posttransplant is superior to BPAR in the first year posttransplant in graft loss prognostic performance, providing valuable additional information and facilitating the demonstration of superiority of novel immunosuppressive regimens.

Quantifying Clinical Trial Diversity in Pivotal Registration Trials of FDA Novel Drug Approvals.

BACKGROUND: Health care inequity includes the lack of adequate representation of various populations in clinical trials. Government, academic and industry organizations have highlighted these issues and committed to actions to improve. In order to assess the current status and future success of these initiatives a quantitative objective measure to assess the state of clinical trial diversity is needed. METHODS: FDA review documents for all novel drug approvals from January 2022 through March 2023 were assessed using a scorecard that considers diversity across different demographic subgroups including age (≥ 65 years old), sex (female), race (Black and Asian) and ethnicity (Hispanic/Latino). The scorecard assigns each drug a letter grade, between A and F, for each subgroup (and overall) based on (1) the percent of each sub-population included in the trials and grades relative to the percent of the US population per the 2020 Census, (2) the number of participants from each subpopulation that received the novel new drug in the trials, (3) the incidence or prevalence of the disease/condition in each of the sub-populations. RESULTS: The FDA approved 49 novel new drugs for 50 indications (one drug was simultaneously approved for two indications). There was good representation of elderly and females with only two drugs receiving a D grade in either of these sub-populations. In contrast, Black (5 F grades) and Hispanic (4 F grades) representation was often inadequate. There were 10 drugs (20.0%) where there were no Black participants receiving the novel new drug and 16 (32.0%) approvals where there were 1-9 Black participants receiving the novel drug. In the Hispanic/Latino population there were 4 (8.0%) approvals with no Hispanic participants receiving the novel drug and 15 (30.0%) approvals where there were 1-9 Hispanic participants receiving the drug. CONCLUSIONS: This scorecard provides an objective quantitative approach to assess the current state of diversity in clinical trials supporting new drug approvals. Substantial improvement in racial and ethnic representation is needed. Meaningful change will require actions and cooperation among all stakeholders to address this multifaceted issue and will take commitment, perseverance, and appropriate incentives.

Applying propensity methods to the United States transplant registry for external real-world evidence control arms for 5-year survival in the BENEFIT study.

To address the challenges of assessing the impact of a reasonably likely surrogate endpoint on long-term graft survival in prospective kidney transplant clinical trials, the Transplant Therapeutics Consortium established a real-world evidence workgroup evaluating the scientific value of using transplant registry data as an external control to supplement the internal control group. The United Network for Organ Sharing retrospectively simulated the use of several distinct contemporaneous external control groups, applied multiple cause inference methods, and compared treatment effects to those observed in the BENEFIT study. Applying BENEFIT study enrollment criteria produced a smaller historical cyclosporine control arm (n = 153) and a larger, alternative (tacrolimus) historical control arm (n = 1069). Following covariate-balanced propensity scoring, Kaplan-Meier 5-year all-cause graft survivals were 81.3% and 81.7% in the Organ Procurement and Transplantation Network (OPTN) tacrolimus and cyclosporine external control arms, similar to 80.3% observed in the BENEFIT cyclosporine treatment arm. Five-year graft survival in the belatacept-less intensive arm was significantly higher than the OPTN controls using propensity scoring for comparing cyclosporine and tacrolimus. Propensity weighting using OPTN controls closely mirrored the BENEFIT study's long-term control (cyclosporine) arm's survival rate and the less intensive arm's treatment effect (significantly higher survival vs control). This study supports the feasibility and validity of using supplemental external registry controls for long-term survival in kidney transplant clinical trials.

Qualifying a Novel Clinical Trial Endpoint (iBOX) Predictive of Long-Term Kidney Transplant Outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

Qualifying a novel clinical trial endpoint (iBOX) predictive of long-term kidney transplant outcomes.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

Pediatric Lung Transplant Outcomes Based on Immunosuppressive Regimen at Discharge: Retrospective Cohort Study Using Real-World Evidence From the US Scientific Registry of Transplant Recipients.

BACKGROUND: This retrospective analysis of the US Scientific Registry of Transplant Recipients was undertaken to obtain real-world evidence concerning the efficacy and safety of tacrolimus-based immunosuppression in pediatric lung transplant recipients to support a supplemental New Drug Application. METHODS: Overall, 725 pediatric recipients of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for up to 3 years post-transplant based on an immunosuppressive regimen at hospital discharge: immediate-release tacrolimus (TAC)+mycophenolate mofetil (MMF), TAC+azathioprine (AZA), cyclosporine (CsA)+MMF, or CsA+AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 year post-transplant, calculated by Kaplan-Meier analysis. RESULTS: The use of TAC+MMF increased over time. During 2010 to 2017, 91.7% of pediatric lung transplant recipients were receiving TAC+MMF at the time of discharge. The proportion of recipients continuing their discharge regimen at 1 year post-transplant was 83.7% with TAC+MMF and 40.4% to 59.7% with the other regimens. Cumulative incidence of the composite endpoint of graft failure or death at 1 year post-transplant was 7.7% with TAC+MMF, 13.9% with TAC+AZA, 8.9% with CsA+MMF, and 9.1% with CsA+AZA. There was no significant difference in the risk of graft failure or death at 1 year post-transplant between groups from 1999 to 2005 (the only era when adequate numbers on each regimen allowed statistical comparison). No increase in hospitalization for infection or malignancy was seen with TAC+MMF. CONCLUSION: The real-world evidence from the US database of transplant recipients supported the Food and Drug Administration's approval of tacrolimus-based maintenance immunosuppression in pediatric lung transplant recipients.

Longitudinal estimated glomerular filtration rate (eGFR) modeling in long-term renal function to inform clinical trial design in kidney transplantation.

Kidney transplantation is the preferred treatment for individuals with end-stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post-transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post-transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well-known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post-transplant. Our model is a nonlinear, mixed-effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long-term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long-term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post-transplant in various clinically relevant populations.

COVID-19 vaccine associated transverse myelitis-Evusheld as an option when vaccination is not recommended due to severe adverse events.

Individuals who experience severe COVID-19-vaccine-related adverse reactions such as transverse myelitis may be precluded from receiving further vaccination to protect from SARS-CoV-2 infection. Although the mechanism of autoimmune spinal cord inflammation resulting in transverse myelitis is unclear, it may be safe to administer antibody therapy for preventing COVID-19. Recently, Evusheld, tixagevimab with cilgavimab, two spike-protein directed monoclonal antibodies were authorized by the U.S. FDA and U.K. MHRA for administration to individuals when vaccination is not recommended. We report the safe administration of Evusheld to a patient who experienced transverse myelitis 11 months previously as a result of receiving the Moderna mRNA vaccine. This patient has experienced no adverse events to Evusheld. Additional experience and data collection are warranted to determine the safety of this prophylactic therapy.

In vitro effect of a non-immunosuppressive FKBP ligand, FK1706, on SARS-CoV-2 replication in combination with antivirals.

FKBP, a naturally occurring ubiquitous intracellular protein, has been proposed as a potential target for coronavirus replication. A non-immunosuppressive FKBP ligand, FK1706, was studied in vitro in a Vero cell model to assess potential activity alone and in combination with antivirals against SARS-CoV-2 replication. When combined with remdesivir, synergistic activity was seen (summary synergy score 24.7±9.56). FK1706 warrants in vivo testing as a potential new combination therapeutic for the treatment of COVID-19 infections.

Lung Transplant Outcomes in Adults in the United States: Retrospective Cohort Study Using Real-world Evidence from the SRTR.

BACKGROUND: The Scientific Registry of Transplant Recipients was retrospectively analyzed to provide real-world evidence of the efficacy and safety of tacrolimus-based immunosuppressive regimens in adult lung transplant recipients in the United States. METHODS: Adult recipients (N = 25 355; ≥18 y) of a primary deceased-donor lung transplant between January 1, 1999, and December 31, 2017, were followed for 3 y posttransplant based on immunosuppressive regimen at discharge: immediate-release tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), cyclosporine (CsA) + MMF, or CsA + AZA. The primary outcome was the composite endpoint of graft failure or death (all-cause) at 1 y posttransplant (calculated via a modified Kaplan-Meier method). RESULTS: Discharge immunosuppressive regimens in lung transplant recipients changed over time, with a substantial increase in the use of TAC + MMF. TAC + MMF was the most common immunosuppressive regimen (received by 61.0% of individuals at discharge). The cumulative incidence of graft failure or death at 1 y posttransplant in adult lung transplant patients receiving TAC + MMF was 8.6% (95% confidence interval 8.1-9.1). Risk of graft failure or death was significantly higher in adults receiving CsA + MMF or CsA + AZA compared with TAC + MMF, with no significant difference seen between TAC + MMF and TAC + AZA. TAC + MMF had the highest continued use at 1 y posttransplant (72.0% versus 35.4%-51.5% for the other regimens). There was no increase in the rate of infection or malignancy in the TAC + MMF group. CONCLUSIONS: Real-world evidence from the most comprehensive database of transplant recipients in the United States supports the use of TAC in combination with MMF or AZA as maintenance immunosuppression in adult lung transplant recipients.

Meeting report: FDA public meeting on patient-focused drug development and medication adherence in solid organ transplant patients.

The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other patient representatives. The morning sessions focused on the impact of organ transplantation on patients' daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful.

Use of low-dose tacrolimus and associated hypomagnesemia in the prevention of erectile dysfunction following prostatectomy for prostate cancer.

BACKGROUND: Hypomagnesemia with urinary magnesium wasting is a well described adverse event with calcineurin inhibitor therapy. Prostate cancer is the most prevalent cancer in men in the United States. Injury to the cavernous nerves during radical prostatectomy frequently results in erectile dysfunction. Tacrolimus has been shown to be neuroprotective in the rat cavernous nerve injury model, an animal model representative of the neural injury that occurs in humans at the time of radical prostatectomy. METHODS: In a randomized, double-blind, placebo-controlled trial, the utility of tacrolimus was assessed for prevention of erectile dysfunction following bilateral nerve-sparing radical prostatectomy. RESULTS: Low dose tacrolimus, associated with low trough levels, resulted in mild hypomagnesemia, which was an early and persistent finding. As early as one week after institution of therapy, mean and median serum magnesium levels were significantly lower in the tacrolimus arm as compared to the placebo arm (p<0.001 for both). While the mean and median levels were within the normal range at Week 1, 10.9% of tacrolimus-treated patients had levels <1.8mg/dL, compared to none in the placebo arm (p=0.017). Median and mean levels remained significantly different at Week 5, Month 3 and Month 6. No clinical manifestations of hypomagnesemia were noted and no subject required treatment with magnesium. Changes in serum magnesium occurred earlier than other potential metabolic adverse events described with tacrolimus (changes in serum glucose, creatinine or potassium). CONCLUSIONS: These data indicate that mild hypomagnesemia is an early and sensitive biomarker for the effect of tacrolimus on the kidney.

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus.

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients.

BACKGROUND: In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported. METHODS: Evaluations included patient and graft survival, study drug discontinuations, laboratory values including renal function and development of new-onset diabetes after transplantation, concomitant medications, and adverse events. RESULTS: At study termination, 129 Astagraf XL, 113 Prograf, and 79 CsA patients had continued follow-up. Demographic and baseline characteristics were similar in all arms. Four-year Kaplan-Meier estimates of patient survival in the Astagraf XL, Prograf, and CsA groups were 93.2, 91.2, and 91.7%, respectively, while graft survival was 84.7, 82.7, and 83.9%, respectively. At least one serious adverse event was reported in the majority of patients in each group during the study (65.9% Astagraf XL, 69.8% Prograf, and 65.6% CsA). Renal function was not significantly different between Astagraf XL and Prograf. HgbA1c levels were collected every 6 months; the 4-year Kaplan-Meier estimate for incidence of HgbA1c levels ≥ 6.5% was significantly higher for both tacrolimus formulations compared to CsA; 41.1% (Astagraf XL), 33.6% (Prograf), and 21.3% (CsA). CONCLUSIONS: In this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new-onset diabetes after transplantation but superior renal function compared to patients receiving CsA.

New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials.

BACKGROUND: New-onset diabetes after transplantation (NODAT) occurs commonly. Prior NODAT definitions have been inconsistent. Based on the American Diabetic Association criteria, we propose a new approach to defining NODAT. METHODS: Analysis of 1416 at-risk transplant recipients was performed. Data from three de novo Astellas registration transplant studies (two kidney and one liver) evaluated NODAT in 634 at-risk patients receiving tacrolimus, 630 at-risk patients receiving tacrolimus extended release, and 152 at-risk patients receiving cyclosporine. NODAT was defined as a composite endpoint consisting of first occurrence of one of four parameters: (i) two fasting plasma glucose levels ≥ 126 mg/dL (≥ 7.0 mmol/L) ≥ 30 days apart, (ii) oral hypoglycemic agent use for ≥ 30 consecutive days, (iii) insulin therapy for ≥ 30 consecutive days, and (iv) hemoglobin A1c ≥ 6.5%. We evaluated each of the above parameters, as well as the composite endpoint, in an attempt to establish an appropriate clinical approach to the diagnosis of NODAT. RESULTS: The composite definition results in a 1-year NODAT incidence of 30% to 37% in kidney and 44% to 45% in liver transplant recipients treated with tacrolimus. NODAT incidence was significantly higher with tacrolimus than cyclosporine; there was no difference between the two tacrolimus formulations. CONCLUSIONS: Based on these analyses, the proposed composite definition for NODAT, incorporating broader criteria, is recommended for clinical trials. Appropriate definitions of NODAT allow for a better understanding of the incidence of this complication and may result in earlier initiation of therapy with improved long-term outcomes.

Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial.

Hepatitis C virus (HCV)-induced cirrhosis is the commonest indication for orthotopic liver transplantation, but HCV recurrence is nearly universal and may worsen patient / graft outcomes. The frequency and severity of HCV recurrence has apparently increased in recent years, raising concern about a possible role for newer immunosuppression regimens in this increase, including potentially tacrolimus. We randomized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation. A pathologist blinded to treatment reviewed serial liver biopsies. Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus- and cyclosporine-treated patients were .38 and .54 (P = .19) and failure / death were .25 and .28, respectively (P = .789). Although cyclosporine-treated patients had significantly larger increases in median serum HCV RNA levels (months 1, 6, and 12), no significant differences were observed between the two treatment arms in histologically-diagnosed HCV recurrence / survival rates. In conclusion, choice of calcineurin inhibitors does not impact severity of recurrent HCV.

New drugs to improve transplant outcomes.

Fujisawa is committed to improving the outcomes of transplant patients worldwide. Research and development programs are underway for a new modified release dosage form of tacrolimus (MR-4), a new analog of leflunomide (FK 778), and several novel compounds (PG 490-88, AGI 1096) in collaboration with other companies. These programs are targeted to address many of the unmet medical needs in transplantation including (1) improving compliance, (2) reducing chronic rejection, and (3) improving long-term safety by reducing infectious and cardiovascular risk.

Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: three-year results.

BACKGROUND: Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell-depleting and interleukin-2 receptor antibodies. METHODS: A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years. RESULTS: At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell-depleting antibody induction (36.1%) when compared with those receiving anti-interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001). CONCLUSIONS: Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell-depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.